Trabecular bone consists of a three-dimensional gridwork whose individual components (the trabeculae) are plates and struts 100-300 .mu.m thick with the mean intertrabecular space varying between about 500 and 1500 .mu.m. The function of the trabecular structure is to provide the skeleton with mechanical strength. Trabeculation is reduced with a concomitant loss in bone strength as a result of normal aging and disease processes such as osteoporosis.
The most common method of assaying bone density is based on a measurement of the X-ray attenuation coefficient using either a projection technique (X-ray dual photon absorptiometry) or its tomographic analog, quantitative computed tomography (QCT). Although these techniques are capable of providing bone mineral densities, they do not provide information on trabecular microstructure (i.e., the geometry, thickness, orientation and density of the trabecular plates), which is commonly obtained by optical stereology, whereby thin sections of transiliac bone biopsy specimens are microscopically analyzed. There is currently no known noninvasive method for obtaining detailed information on trabecular microstructure.
Osteoporosis is a widespread disease predominantly afflicting postmenopausal women. It is a complex, multifactorial, chronic disease that may be silent for decades until resulting in fractures late in life. As a result of demineralization and gradual depletion of the trabecular microstructure, the weight-carrying capacity of the bone decreases, leading to atraumatic fractures. The two currently used methods for diagnosis and therapy follow-up are single or dual photon absorptiometry (SPA and DPA, respectively) and QCT. Those methods, however, are invasive in that they use ionizing radiation and their scope is limited in that they only measure bone mineral density (BMD), while ignoring the morphology of the trabecular structure. Moreover, those methods fails to take into account the physiological and/or biochemical state of the marrow.
The definition and diagnosis of osteoporosis has generally focused on bone density because that is the only parameter that has been quantitated in vivo. However, resistance to fracture (i.e., mechanical strength) is a function of the structural arrangement of the bone as well as the bone's density. Most osteoporotic fractures occur in the regions of the skeleton with a high proportion of trabecular bone. A high correlation has been found between vertebral body compressive strength and the density of the trabecular bone; (R=0.91 in one study, McBroom, R. J. et al., "Prediction of Vertebral Body Compressive Fracture Using Quantitative Computed Tomography," J Bone Joint Surg (1985) G7A:1206-1214; and R=0.87 in another, Eriksson S. A. V., Isberg B. O. and Lindgren J. U., "Prediction of Vertebral Strength by Dual Photon Absorptiometry and Quantitative Computed Tomography," Calcif Tissue Int (1989) 44:243-250. Measurements using QCT (R=0.47) and DPA (R=0.74) are less predictive. This relationship may be even weaker in patients with osteoporosis since this disorder is accompanied by an unpredictable disruption of the trabecular architecture.
Histomorphometric information may be obtained in vitro by means of scanning electron microscopy of bone specimens. Histomorphometric studies of iliac crest biopsies have shown that the loss of trabecular bone may be the result of a loss of trabeculae or a thinning of individual trabecular plates. See Kleerekoper, M. et al., "The Role of Three-dimensional Trabecular Microstructure in the Pathogenesis of Vertebral Compression Fracture," Calcif Tissue Int (1985) 37:594-597; Parfitt, A. M. et al., "Relationships Between Surface, Volume, and Thickness of Iliac Trabecular Bone in Aging and in Osteoporosis," J CIin Invest (1983) 72:1396-1409. Researchers have found that increased trabecular spacing accounted for 67% of the decrease in bone volume with age, while 33% was due to trabecular thinning. See Weinstein, R.S. and Hutson, W. S., "Decreased Trabecular Width and Increased Trabecular Spacing Contribute to Bone Loss with Aging," Bone (1987) 9:137-142. Patients with vertebral compression fractures have been shown to have a lower trabecular plate density in biopsies of their iliac crest than osteoporotics with similar bone mineral densities (BMD's). See Kleerekoper, M. et al., "The Role of Three-dimensional Trabecular Microstructure in the Pathogenesis of Vertebral Compression Fractures," referenced above. The latter study suggests that heterogeneity with respect to trabecular plate density may account for some of the variance in fracture incidence.
Whereas with current technology bone is almost inaccessible to in vivo magnetic resonance imaging as a result of its unfavorable relaxation properties (in solids: T1.about.10.sup.1 -10.sup.2 sec, T2&lt;&lt;1 msec), bone marrow has been studied extensively by bulk proton imaging. See Dooms, G. C. et al., "Bone Marrow Imaging: Magnetic Resonance Studies Related to Age and Sex," Radiol (1985) 155:429-432; Pettersson, H. et al., "MR Imaging of Bone Marrow in Children: Magnetic Resonance Relaxation Characteristics of Muscle, Fat and Bone Marrow of the Extremities," JCAT (1986) 10:205-209; LeBlanc, A.D. et al., "The Spine: Changes in T2 Relaxation Times from Disuse," Radiol (1988) 169:105-107; Bloem, J. L., "Transient Osteoporosis of the Hip: MR Imaging," Radiol (1988) 169:753-755.
Bone marrow has also been studied with spectroscopy and spectroscopically resolved imaging. See, Luyten, P. R., Anderson, C. M. and den Hollander, J. A., "HNMR Relaxation Measurements in Human Tissues In Situ by Spatially Resolved Spectroscopy," Magn Res Medicine (1987) 4:431-440; Richards, T. L. et al., "Lipid/Water Ratio of Bone Marrow Measured by Phase-encoded Proton Nuclear Magnetic Resonance Spectroscopy," Invest Radiol (1987) 22:741-746; Rosen, B. R. et al., "Hematologic Bone Marrow Disorders Quantitative Chemical Shift Imaging," Radiol (1988) 169:799-804.
The large range in the apparent proton spin-lattice (T1) and spin-spin (T2) relaxation times reported has been attributed to changes in fat/water composition of the marrow since T1,2(fat)&lt;&lt;T1,2(water). Aging has been found to be associated with a decrease of the apparent T1 and T2 relaxation times, presumably as a consequence of replacement of hematopoietic marrow by fatty marrow. See Dooms, G. C. et al., "Bone Marrow Imaging: Magnetic Resonance Related to Age and Sex," Radiol (1985) 155:429-432; Richards, M. A. et al., "In Vivo Measurement of Spin-lattice Relaxation Time (T1) of Bone Marrow in Healthy Volunteers: The Effects of Age and Sex," Br J Radiol (1988) 61:30-33.
An attempted direct NMR measurement of the .sup.31 P resonance showed that the phosphate resonance in calcium hydroxy apatite, the mineral constituent of bone, can be detected by high-resolution NMR and that it is conceivable to integrate the signal and determine the absolute concentration by calibration against a reference standard. However, this technique merely duplicates BMD measurements by QCT or absorptiometry. See, Brown et al., "Noninvasive Evaluation of Mineral Content of Bone Without the Use Ionizing Radiation," CIin Chem (1987) 33:2272236.
Thus, despite extensive study of trabecular bone and the causes of osteoporosis, there is no known method of characterizing the trabecular bone structure in vivo.